Thrombolysis increases the risk of persistent headache attributed to ischemic stroke: A prospective observational study

Abstract Background and objective Persistent headache attributed to ischemic stroke (PHPIS) is increasingly acknowledged and was added to the 2018 ICHD‐3. Intravenous thrombolysis (IVT) is a common treatment for acute ischemic stroke. It remains unknown whether this treatment influences the occurrence of a persistent poststroke headache. We aimed to describe the incidence and clinical characteristics of persistent headaches occurring after acute ischemic stroke in patients with or without IVT and explore the risk factors. Methods A prospective observational study was performed between the 234 individuals who received IVT and 226 individuals without IVT in 5 stroke units from Wuhan, China. Subjects were followed for 6 months after stroke via a structured questionnaire. Results Age, gender, vascular risk factors, and infarct location/ circulation distribution did not differ between the groups, although IVT group had higher initial NIHSS scores. At the end of the follow‐up, 12.0% (55/460) of subjects reported persistent headaches after ischemic stroke. The prevalence of persistent headache was significantly higher in the IVT group than non‐IVT group (15.4% vs. 8.4%, p = .021). Patients with younger age (p = .033; OR 0.97; 95% CI 0.939–0.997), female sex (p = .007; OR 2.40; 95% CI 1.269–4.520), posterior circulation infarct (p = .024; OR 2.19; 95% CI 1.110–4.311), and IVT (p = .005; OR 2.51; 95% CI 1.313–4.782) were more likely to develop persistent headache after ischemic stroke. Conclusion The potential influence of IVT should be considered when assessing persistent poststroke headache. Future studies will investigate the underlying mechanisms.


INTRODUCTION
Stroke is the leading cause of death and disability worldwide (Wang et al., 2017).Headache is a common symptom or even a complicating disease secondary to the stroke attack (Harriott et al., 2020).
Both stroke and headache cause neurological disability, and the occurrence of poststroke headache is associated with a lower quality of life (Tabeeva, 2021;Westerlind et al., 2020).Poststroke headache is a type of headache attributed to a stroke, which typically develops in temporal relation to the onset of the stroke and significantly worsens or improves in parallel with the worsening or improvement of the stroke.
In the literature, 33.5% of stroke patients experienced a headache at stroke onset, 7-23.0%had persistent headaches for 3 months, and early emergence of headaches predicted persistent headaches at 6 months (Lai et al., 2018).The persistent headaches still exist although the stroke is improved.In the 2018 International Classification of Headache Disorders, 3rd edition (ICHD-3), this has been termed as "persistent headache attributed to past ischemic stroke" (PHPIS), which is a subset of headaches that begins at stroke onset and continues months to years thereafter (Olesen et al., 2018).As a new type of headache, the knowledge of PHHIS is still poor.
Intravenous thrombolysis (IVT) is a major therapeutic modality in acute ischemic stroke (Powers et al., 2019).IVT can restore blood supply, reduce neural injury, significantly relieve symptoms at the acute stage, and improve long-term prognosis (Goyal et al., 2015;Todo et al., 2019).However, it also increases the risk of intracerebral hemorrhage and ischemia-reperfusion injury (Demaerschalk, 2007;Ferro et al., 2021;Ng et al., 2021) may be through promoting inflammation (Dodick, 2018;Harriott et al., 2020), vascular endothelial damage (Leira et al., 2002) and free radicals (Oztanir et al., 2014;Sladojevic et al., 2014).Therefore, the IVT was supposed to predispose the appearance of PHPIS and act as a risk factor.Here, we performed an observational study in objects with IVT or not, to examined the prevalence, clinical characteristics, and risk factors of PHPIS, and find the correlations between IVT and PHPIS.

Participants
A prospective observational study was performed on inpatients from 5 stroke units in Wuhan, China, during the period spanning October This study was approved by the Ethics Committee of Tongji Hospital (No. TJ-IRB20210107) and conducted according to the Declaration of Helsinki.According to ethics guidelines, the requirement of written informed consent was waived because anonymization was used in this observational study and there was no risk of harm to the patients.
According to the Chinese Stroke Association guidelines (Liu et al., 2020), which is similar to the guidelines from the American Heart Association/American Stroke Association (Powers et al., 2019), acute ischemic stroke patients received IVT using recombinant tissue plasminogen activator (rt-PA, alteplase, 0.9 mg/kg, maximum dose 90 mg, over 60 min with initial 10% bolus over 1 min).These patients were enrolled in the IVT group, while others were included in the non-IVT control group (Figure 1).

Clinical assessments
The ( Yoo et al., 2016).Brain CT and/or MRI on admission were used to classify the distribution of infarcts according to anatomical and vascular distribution (anterior circulation: middle and anterior cerebral artery, posterior circulation: posterior cerebral artery, or both).

Headache assessments
With face-to-face interviews by a trained neurologist who has been blinded, characteristics of headaches were recorded on the admission and in the third and sixth month postischemia, followed by online interviews later.A standardized questionnaire (Table S1) was prepared as previously reported (Olesen et al., 2000), which records the cause, characteristics (location, intensity, headache type, concomitant symptoms, and daily influence) (Olesen et al., 2018), and headache treatments used before stroke, during acute stroke, and after stabilization (dominant symptoms stop getting worse).Standard evaluations including the Visual Analogue Scale (VAS) and Headache Impact Test-6 (HIT-6) were performed to determine the severity and impact of poststroke headache on daily life (Aicher et al., 2012;Haywood et al., 2021).
According to the 2018 ICHD-3 Code 6.1.1.2,PHPIS is defined as the development of headache simultaneously with or in close temporal relationship to signs or other evidence of ischemic stroke confirmed by imaging and clinical symptoms, the persistence of symptoms for more than 3 months, and the lack of another ICHD-3 diagnosis that would better account for the occurrence of persistent headache.The diagnosis of PHPIS was given after 6 months of follow-up.Headache was described as migraine-like (referring to Code 1.5), tension-type headache-like (referring to Code 2.4), or others (Olesen et al., 2018).
The characteristics of headaches were described as follows.The appearance of the first attack was grouped according to the initial time after ischemia, within 1 h, 1-24 h, or 24 h later.The location of the headache was categorized as left, right, or bilateral.The quality of headache was categorized as pulsating, tension-type, throbbing, or other.Accompanying phenomena like nausea, photophobia, phonophobia, and dizziness were recorded.The frequency of headache was classified as less than 7, 7-14, or more than 14 headache days per month.The intensity of headache was graded as mild (VAS ≤ 3), moderate (VAS = 4-6), or severe (VAS ≥ 7) pain (Collins et al., 1997).
Medications were monitored to account for possible medication overuse headache (ICHD-3 Code 8.2) (Olesen et al., 2018).Typical treatments for ischemia and its comorbidities were given according to the guidelines from the Chinese Medical Association and National Institutes of Health (USA).Medications (like dipyridamole and cilostazol) and paregorics that might influence the headache were recorded (Westergaard et al., 2014).Although neuropsychological disorders are not quantified by scales, possible events were recorded to estimate the influence on the headache.

Statistical analysis
The sample size was based on the available data and no statistical power calculation was done upfront.This was the primary analysis of our collected data.Statistical analyses were performed using the An internal validation using a bootstrap resampling process was conducted to evaluate the performance of this model.Multicollinearity was confirmed to be absent by a variance inflation factor of less than 10 across all variables.Odds ratios (ORs) and 95% confidence intervals (CIs) of variables were determined.p < .05 was considered to indicate statistical significance.
The demographics and clinical characteristics of the two groups are presented in Table 1.When comparing between IVT and non-IVT groups, no statistical differences were found in age, gender, medical history (hypertension, hyperlipemia, diabetes, atrial fibrillation, previous stroke, smoking, and alcohol intake), infarct location, and vascular distribution.The IVT group had higher initial NIHSS and ASPECT scores compared with that in non-IVT group (p < .05).

Risk factors for PHPIS
Traditional vascular risk factors such as hypertension, hyperlipemia, diabetes, atrial fibrillation, previous stroke, smoking, and alcohol intake did not differ between subjects who developed PHPIS and those who did not.The initial NIHSS and ASPECTS also did not differ.In contrast, females, subjects who received IVT, and posterior circulation

DISCUSSION
Headache is a common but under-appreciated symptom in ischemic stroke patients.A 10-12% prevalence of persistent headache after stroke has been detected in observational studies spanning 16 months (Jonsson et al., 2006) to 3 years after stroke (Hansen et al., 2015), although the prevalence appeared to decrease over time (Naess et al., 2010;Osama et al., 2018).In this study, headache was observed in 25.2% of patients after ischemia, and 12.0% were diagnosed with PHPIS after 3 months of follow-up in the present study.
The characteristics of headaches following an ischemic stroke usually vary.In our study, patients mostly experienced mild headaches lasting no more than 24 h, had migraine or tension-type-like headaches, and rarely reported substantial impact on daily life.This is consistent with previous reports, where 50.0% of headaches were tension-typelike (Hansen et al., 2015), and usually mild (Carvalho Dias et al., 2020), although moderate to severe pain was also experienced (Jonsson et al., 2006).Accompanying symptoms like nausea/vomiting, phonophobia, and photophobia were reported (Hansen et al., 2015).Interestingly, dizziness was a frequent symptom accompanying headaches especially in IVT patients in the present study.Although medication overuse was previously reported in 6.25% cases with persistent headache following stroke (Hansen et al., 2015), and even 30% of cases with persistent headache after first-ever ischemic stroke (Lebedeva et al., 2022), analgesic drugs were rarely taken by patients in this Chinese cohort.Patients with mild or moderate headaches usually did not take analgesics.The difference in population and culture should also be considered since the prevalence of medication overuse headache is intrinsically lower in China (Dong et al., 2015).
We also found that posterior circulation was associated with the PHPIS.Individuals with vertebrobasilar stroke were noted to have a higher probability of stroke-related headache (Seifert et al., 2018).
These findings suggest that infarct distribution is an important determinant for stroke-associated headache.The reasons for this are not clear but may be related to perivascular innervation in posterior locations such as the trigeminal nucleus and thalamus.In another study using lesion mapping in the acute phase of stroke, individuals with lesions located in the insular cortex/cerebellum and somatosensory cortex were likely to have poststroke headache (Osama et al., Seifert et al., 2018).Ischemia might lead to dysfunction of the trigeminal nerves, serotonergic nuclei in the brainstem, somatosensory cortex, and even pain-sensitive structures like dura mater, leading to headache (Kim et al., 2008;Mitsias et al., 2006).Furthermore, following ischemia, persistent chronic headaches may be linked to central sensitization of pain pathways (Woolf, 2011).
There are several limitations to the present study.First, without a randomized controlled design, the influence of IVT on PHPIS could not be directly tested by fully evaluating confounders.Second, although a multiple regression analysis accounting for age, sex, hypertension, hyperlipemia, diabetes, atrial fibrillation, previous stroke, smoking, alcohol intake, NIHSS and ASPECT, IVT, and arterial territory was carried out, new protocols are needed to evaluate these factors and other potential confounders (e.g., lesion size and detailed headache history).Third, bias may have resulted from limited cohort size and exclusions.Fourth, regional and ethnic differences were not observed in the present study.

CONCLUSIONS
We found that IVT was an important risk factor for the presence of PHPIS.Although the pain is usually mild-to-moderate and has limited influence on daily life, more attention must be paid to this newly recognized headache.Future studies will explore possible mechanisms utilizing, for example, transcranial Doppler ultrasound and functional MRI and identify prevention and treatment options for of IVT-related persistent headaches.
Demographics and clinical characteristics.
TA B L E 1Abbreviations: ASPECT, Alberta Stroke Program Early CT Score; IVT, intravenous thrombolysis; NIHSS, National Institute of Health stroke Scale.ap < .05 vs. non-IVT group.IBM SPSS statistical package (version 25.0, IBM Corp., Armonk, NY, USA).Continuous variables consistent with normal distribution were compared via independent-sample t-test, and results were reported as mean ± standard deviation (SD).Continuous variables without normal distribution were compared via the Mann-Whitney U test, and results were represented by median and interquartile range.Categorical variables were analyzed by chi-square test or Fisher's test, and results were reported as numbers and percentages.Baseline variables that were considered clinically relevant or that showed univariable relationships with the dependent variables were entered into multiple regression.Binary logistic regression analysis was performed using backward elimination to evaluate possible risk factors for headache.
Characteristics of PHPIS.
(VAS score), frequency, location, quality, or influence on daily life (HIT-6 score).In the IVT group, persistent headaches were more likely to be initiated during the first day after stroke onset inIVT (38.9%)than non-IVT group (10.5%).Headaches in the IVT group were more likely to be characterized as moderate-severe intensity, bilateral, and TA B L E 2 47/55) lasted less than 24 h and had limited influence on daily life (Table2).Only 6 (10.9%) cases took analgesics during some attacks and no medication overuse headache was documented.
Risk factors for PHPIS.Alberta Stroke Program Early CT Score; IVT, intravenous thrombolysis; NIHSS, National Institute of Health stroke Scale; PHPIS, persistent headache attributed to past ischemic stroke.Stepwise multiple regression analysis for risk factors.Table 4, see Table S2 for details).
TA B L E 3 a p < .05 vs. nonheadache group.TA B L E 4